Action Points

Note that patients taking ranolazine had lower weekly sublingual nitroglycerin use compared with those in the placebo group and that ranolazine was not associated with a significantly higher incidence of serious adverse events.

The use of ranolazine (Ranexa) in diabetic patients with documented coronary artery disease and stable angina resulted in a significant reduction in average weekly chest pain episodes compared with placebo at 8 weeks (3.8 versus 4.3, P=0.008), reported Mikhail Kosiborod, MD, of the University of Missouri's St. Luke's Mid America Heart Institute in Kansas City, and colleagues.

The patients in the treatment arm also had a significantly lower average weekly use of sublingual nitroglycerin compared with placebo (1.7 versus 2.3 doses, P=0.003), they reported online in the Journal of the American College of Cardiology.

The weekly episodes of chest pain in the ranolazine group also had decreased to a greater extent from baseline compared with placebo (from 6.6% to 3.8% and from 6.8% to 4.3%).

Gordon Tomaselli, MD, from Johns Hopkins University and former president of the American Heart Association, called the results encouraging.

"We use this drug a lot in various anti-angina scenarios. The use in patients with type 2 diabetes is an experimental use, but it's gratifying that there is another agent out there for a disease that is difficult to manage," said Tomaselli, who was not involved in the study. The next step is to determine whether the drug makes a difference in clinical outcomes.

"Every time you have an angina episode, there is a potential for something worse to happen," Tomaselli noted. "If we reduce the frequency of those episodes, we can reduce the frequency of the complication of those attacks, whether it is arrhythmia or thrombosis."

Interestingly, Kosiborod and colleagues noted that "the therapeutic superiority of ranolazine on reducing weekly angina frequency was more pronounced in patients with higher baseline HbA1c levels, regardless of the HbA1c cutpoint used" (P=0.027 for interaction).

The mechanism underlying the bump in ranolazine's effectiveness in diabetics is unclear, but they noted that cardiomyocytes exposed ex vivo to high glucose have upregulation of a kinase known to phosphorylate the cardiac sodium channel.

This may result in "increased late sodium current, thereby leading to increases in intracellular sodium and calcium. Ranolazine, an inhibitor of [late sodium current], would then be expected to have a greater therapeutic effect in patients with poor glycemic control," they added.

The investigators pointed out that ranolazine is not specifically indicated for control of angina in patients with type 2 diabetes. These patients are "unique in many ways, partly because they are at high risk to have a greater burden of coronary disease and a greater burden of angina than patients without diabetes."

Three ongoing clinical trials will help clarify the glucose lowering properties of ranolazine, he mentioned.

To potentially add to the evidence that this drug has anti-anginal effects, researchers designed the randomized, double-blind TERISA trial.

Patients recorded anginal episodes and nitroglycerin use daily in an electronic diary (98% capture in both groups). The primary outcome was the number of anginal episodes over the last 6 weeks of the study.

The mean age of patients was 64, the majority were men (61%), the mean duration of diabetes was 7.5 years, and the mean baseline glycated hemoglobin (HbA1c) was 7.3%.

A total of 93% of patients were treated with glucose-lowering medications, including 19% treated with insulin. Regarding anti-anginal medication, 56% of patients were taking one agent at baseline, while the remainder were on two agents.

Seventy percent of patients were enrolled in Russia, Ukraine, and Belarus, and 30% were enrolled in other countries.

Although the average number of weekly angina episodes during the treatment phase decreased significantly in both groups, results of the treatment and placebo arms were similar in those enrolled from Russia, Ukraine, and Belarus (4.1 versus 4.3, P=0.31).

However, the difference between the two arms among those enrolled in other countries was significant (3.1 versus 4.1, P=0.002).

There was no difference in the incidence of serious adverse events between groups, the authors reported.

The study had some limitations, most notably that 99% of the patients were white, limiting the application of the results to a more racially diverse population. Also, the findings of greater ranolazine efficacy in patients with higher HbA1c were adjusted for several factors including geographic region, but there was still the possibility of residual confounding.

Lastly, the relatively short duration of treatment in TERISA did not address the durability of the observed anti-anginal effect of ranolazine.

Saint Luke's Mid America Heart Institute received funding for the independent statistical analysis of the TERISA trial from Gilead Sciences and has received funding from the company for research not related to TERISA.

Kosiborod reported research support from Gilead Sciences unrelated to TERISA along with research support from the American Heart Association (AHA), Medtronic Minimed, Genentech, sanofi-aventis, and Glumetrics. He is a consultant for Gilead Sciences, Genentech, Hoffman-La Roche, Boehringer-Ingelheim, Medtronic Minimed, and CardioMEMS.

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